3-carboxy-4-alkoxy-diphenyl and salts thereof



Patented Aug. 7, 1934 1,969,354

UNITED STATES PATENT. OFFiCE '3-CAREOXY-4-ALKOXY-DIPHENYL AND a SALTS THEREOF Walter G. Christiansen, Glen Ridge, N. J;, and

1 Adelbert W. Harvey, Pittsburgh, Pa., assignors p to E. R. Squibb & Sons,'Brooklyn, N. Y., a cornotation of New York No Drawing. Application August 6, 1932,

, Serial No. 627,806

13 claims. .(01. 260-111) This invention relates to 3-carboxy-4-alkoxyfree flame or by any other suitable method of diphenyls and salts thereof, and more particuevaporation. Care should be taken to prevent larly to the ethoxy and butoxy derivatives and absorption of carbon dioxide by the solution or their alkali metal salts. The invention includes the Wet mass during evaporation. Final drying 1'5 the new products and method of preparing them; of the phenolate is carried out in vacuo, about These compounds are valuable as intermediates mm., at 180 C. for some time, usually 5 hours, in the production of compounds having theraafter no more water is collected in an ice trap. peutic value, particularly anaesthetics. The dry pulverized phenolate is treated with The 3-carboxy-4-alkoxy-diphenyls are advancarbon dioxide in an autoclave at approximately '10 tageously prepared from 3 carboxy-4-hydroxy- 90 pounds per square inch to form the sodium diphenyl which may be prepared by the method salt of 3-carboxy-4-hydroxy diphenyl. The temdisclosed in the application of Adelbert W. Harperature is held at 110-120 C., for 1 hour, invey, Serial No. 615,473, filed June 4, 1932, now creased to 160-170 C., and held at the latter Patent No. 1,941,207 of Dec. 26, 1933. The hydrotemperature for 3-4 hours. The reaction prod- 115 gen of the phenol group and the hydrogen of the uct is placed in 3000-4000 cc. of water, heated to carboxyl group of 3-carboxy-4-hydroxy-diphenyl boiling, and then preferably afterfiltering treatare replaced first by an alkali metal such as sodied with carbon dioxide until no more 4-hydroxyum and then by an alkyl group. This alkyl ester diphenyl is precipitated. The suspension is filis then saponified and the alkoxy'derivative of tered to remove the unconverted 4-hydroxy-dif20 the acid formed. phenyl and the 3-carboxy-4-hydroxy-diphenyl is 7 5 The course of the reaction may be represented precipitated by acidification with mineral acid. by the following series of compounds in which The. product is then. filtered off, washed with Ris an alkyl group: I 7 7 water and dried.

OH n, OR 3 214 grams of 3-carboxy-4-hydroxy-diphenyl,is i535 y converted intothe di-sodium derivative (sodium 000E COONa 000R salt and sodiurnflphenolate) :by'treatment with- 80 grams of sodium-hydroxide dissolved in 3000;.- p 4000 cc. of water. The mixture is boiled until all M of the 3-carboxy-4-hydroxy-dipheny1 has been 30 r I dissolved and is then evaporated ,to dryness. s5

' Final drying is conveniently carried .out by placing in an oven at 105-110 C. for several hours. ,The dry di-sodium compound is treated with 154 grams of ethyl sulfate, or more conveniently with 35 OR OR t a considerable excess over this amount, and heated for 3-4 hours at 145 C. During the early COON COOH stages of heating, at 105-120? 0., asmall quantity of alcohol and ether is distilled ofi after which no further distillation takes place. Care must be "-40 taken to control the temperature to prevent de- 95,

' composition of the ethyl sulfate with possible sulfonation of the 3-carboxy-4-hydroxy or the resulting ethylated derivative. Following the reaction period, the greater part of any excess of ethyl sulfate is removed by distillation in vacuo at a pressure of 13 mm. at about 100 C. The

residue, which consists largely of sodium sulfate to illustrate the preparatlon of the compounds or sodium ethyl sulfate, depending on the excess of this invention, but it is to be understood that of ethyl sulfate used, a small amount of ethyl -50 the mventlon Is not hmlted thereto sulfate and the ethyl ester of 3,-carboxy-4-ethoxy- Example grams of 4"hydmxy'd1pheny1 diphenyl is conveniently separated by boiling is convertedinto the Sodium phenolate by heat with water and mechanical separation of the hot ing to bO l With 40 grams of Sodium hydroxide aqueous solution from the Water insoluble ester.

in 400-600 cc. of solution. The sodium phenolate The free acid, 3-carboxy-4-ethoxy-diphenyl, is ,55 may be recovered by direct evaporation over a made from the ethyl ester by saponification with The preparation of the ethoxy and butoxy derivatives of B-carboxy-diphenyl is given below form.

Example 2.42.8 grams (.0121 mole). of .3 ca-rboxy--hydroxy-diphenyl is converted into'zuthe' di-sodium derivative by treatment With 16 grams of sodium hydroxide dissolved in 600-8010. cc.- of water. The mixture is boiled" untilall" of the 3.- carboxyl-hydroxy-diphenyl has been dissolved and is then evaporated to dryness. Final drying is conveniently carried out by'placingin-anioven at 105-1l0 C. for several hours.

The dry di-sodium compound is treated. with an excess over 54.8 grams (0.4 mole) of n-butyl bromide and heated preferably in a closed vessel in a bath maintained at 130 C. for 5 hours. After cooling, the 11-butyl' ester of 3-carboxy-4-nbutoxy-diphenyl and excess of n-butyl bromide is filtered from the by-product sodium bromide and the excess of n-butyl bromide removed by distillation. The residue consists principally of the n-butyl ester of 3-carboxy-4'-n-butoxy-di-,

phenyl. I

The free-acid, 3-carboxyi-nebutoxy diphenyl, is obtained by saponifioation of its n-butyl ester with dilute aqueous-alcoholic solution of. sodium hydroxide and precipitation of the free acid. from the resulting sodium salt by acidification. with mineral acid, such as hydrochloric acid. Itis preferable'to-remove the greater part of; the-alcohol from the saponification mixture before the acid precipitation.

The compound may be filtered. 01f, dried and purified by crystallization from a mixture of henzene and petroleum ether, or from. approximately (leper cent alcohol". The pure material crystal.- lizes in pure White crystals with a melting point of 835-84' .5"'C1 (corrected). T

The compound is soluble in alcohol,v ether, benizene, chloroform and several other organic sol.-

. vents. It'is useful as an: intermediate in the preparation of local. anaesthetics and other synthetic derivativesj 1 Qther alkoX-y derivatives of 3-c'arboxydiplrenyl may be prepared by using other alkyl. halides or salts such as methyl: sulphate in the preparation of the methoxy derivative and alkyl sulfi'tes or para toluene sulfonates for the preparationof derivatives containing more than two carbon atoms in the alkoxygroup.

Salts of the 3-carboxy-4-al-koxy-diphenyls may The compound is soluble in alcohol, ether, benzene and chloro- I be prepared by dissolving the carboxy acid in a solution containing the chemical equivalent in sodium hydroxide or other suitable alkali and evaporating, to. dryness in case the dry salt is desired, or: using the-solution such if a' solution ofth'e salt is desired.

We claim:

1. A compound having the formula:

. I 000x whereY is analkyl group and X is hydrogen or an alkali. metal.

2;. v3-carboxy 4ealkoxy-diphenyls. 3. 3-carboxy-4-ethoxy-diphenyl. 4.; 3-carboxy-4-n butoxy-diphenyl. 5'; Alkali'metal' salts of the 3-carboxy-4-alkoxy-diphenyls.

6. The sodium salt of 3 carboxy-fl-ethoxy-diphenyl. I

7. Thesodium salt of 3 carboXy-4-n-butoxy 8; The method of preparing3 -c'arboxyl alkoxyd-iphenyls", which comprises converting 3- carboxy-4hydroxy-diphenylto its di-alkali metal derivative, replacing each alkali metal atom by an alkyl group and 'saponifying the resulting ester;- '9; The steps inthe preparation of 3 carb'oxyi-alkox'y-diphenyls'which comprise forming the di-sodium derivative of '3 carboxy-4-hydrox-ydiphenyl by treating 3-carboxyi-hydroxy-di phenyl with sodium hydroxide to form the "di sodium salt and then converting the sodium phenolate to the alkoxy derivative. 1 1

lfiz'Themethod of preparing 3-'carboxy 4'al'- koxy diph'enyls which comprises saponifying an ester of a' 3-carboxy-e-all ioxy-diphenyl; ll; Thestepinthe preparation of 3 carboxylqalkoxy-diphenyls which comprises heating-the di-alkali metal salt 'o'ff-E-carboXy-4' hydroxydi corresponding alkyl halide.

WALTER G. CHRVISTIANSEN. ADELBERT' w; HARVEY. 

